Peter Öhlschläger - New strategies for the treatment of cancer
Professor Peter Öhlschläger established his major scientific interests very early on. During his degree thesis at the German Cancer Research Centre (DKFZ) in Heidelberg, the immunologist succeeded in combining his two major interests, namely virology and cancer. Öhlschläger is now junior professor at the University of Constance and mainly deals with the development of therapeutic cancer vaccines.
“This kind of continuity is quite rare. What people do during their doctoral training often ends up at the back of a cupboard and is rarely used for clinical application,” said Professor Öhlschläger. He is particularly interested in cervical cancer, which is caused by the infection with specific human papillomaviruses (HPV). Nearly all women become infected with at least one HPV type during their lifetime since HPV is typically transmitted through sexual contact. Infection usually goes unnoticed and does not generally lead to any problems. However, HPV can cause persistent infections, which, in combination with other factors such as pregnancy or hormonal contraceptives can potentially lead to abnormal cells in the cervix.
A vaccine against papillomavirus infections (Gardasil®) has been available for young women for the last two years. Although it has many benefits, it also has some serious drawbacks: first, Gardasil® is only effective when used prior to the first sexual contact. This means that already infected women cannot benefit from the vaccine, which, in addition, only provides protection against two of a total of 18 HPV types that can cause cervical carcinoma. Second, the vaccine is relatively expensive, which makes its broad application difficult, in particular in third-world countries where cervical cancer is widespread, as Professor Öhlschläger explains. In addition, it might take twenty years or more from the establishment of a persistent infection with a certain HPV type and the development of cancer. That is why future efforts to improve the treatment of cervical cancer will also be necessary.
Therapeutic cancer vaccination
At present, cervical tumours are usually surgically removed, and surgery is then followed by chemotherapy treatment. This kind of therapy is very unsatisfactory and there is a great need for new therapies, especially in cases where metastases have developed. Professor Öhlschläger is therefore pursuing a different strategy: therapeutic cancer vaccination. “Vaccination alone is not sufficient to successfully treat cancer,” said Öhlschläger, but he is very hopeful about the use of vaccination as a supplementary therapy. The first clinical study will shortly commence.
Öhlschläger’s method is not only new and promising because it can not only be used to treat women who are already infected with papillomaviruses, but also because it involves a new type of vaccine: DNA vaccines. Traditional vaccines are composed of proteins, which are expensive and need to be stored at low temperatures. In contrast, DNA vaccines are stable and cheap and can also be ‘bespoke’ designed for individual cases. The idea of using DNA as a vaccine first arose around 15 years ago and the first DNA vaccines for animals are already on the market. The human application of DNA vaccines is still regarded with scepticism in some quarters and researchers working on this topic are often seen as outsiders. The “trick” of DNA vaccination is that the immunising protein is produced by the body itself. The DNA vaccine contains the information for generating such proteins. However, DNA vaccines have the disadvantage that the immune response is a lot weaker than that obtained with traditional protein-based vaccines.
Professor Öhlschläger has identified a gene in HPV-16, one of two high-risk papillomavirus types. This gene is transcribed in all infected cells. However, this gene, known as E7, cannot be injected into the muscle in order to provoke the desired immune response since it has an oncogenic effect. The immunologist has developed an artificial gene that leads to the same immune response but does not cause cancer. The therapeutic effect has already been shown in animal experiments. In some mice, the gene construct led to the total regression of the tumour. Öhlschläger is now hoping to carry out a clinical study in Heidelberg and at the Charité Hospital in Berlin. The researcher hopes to be able to commence the study at the end of the year. But before that, it is necessary to produce a totally pure vaccine substance under standardised conditions. And this is not possible in the research laboratory at the University of Constance.
The procedure for the approval of the method for human application is lengthy. As this is the first time ever that authorisation to use a DNA vaccine for human therapy has been sought, the Paul Ehrlich Institute, Germany's regulatory authority for biological products, has no comparative data with which to compare Öhlschläger’s data. DNA-based vaccines have already been approved for use in clinical studies in other countries. Despite initial promising successes, the immunologist is always aware of the possibility of drawbacks arising. “There is a high probability that the vaccine will not work at all or at least will not be immediately successful,” said Öhlschläger who does not let this put him off.
Optimism after drawbacks
Instead, he is already focusing on another problem; apart from looking for an effective vaccine against cervical carcinoma, Öhlschläger is also working on therapeutic vaccines against prostate cancer. “It is necessary to pursue several strategies simultaneously in order to come up with a useful result,” said the researcher explaining his modus operandi. A prostate vaccine poses completely new problems. Prostate cancer is not caused by a viral protein, but by a protein that also occurs in other tissues to which the body does not react. “This is a huge challenge. However, if it works, it would also open up ways to develop vaccines for many other cancers.”
After two years of numerous failures and drawbacks, the Constance immunologist is now optimistic, following his success in considerably improving the immune response. The trick is to use “adjuvant genes” that attract important immune cells to the site where the vaccine needs to be applied. This leads to a considerably enhanced immune response. On the other hand, an electrical field leads to the temporary permeability of the cell wall. A major problem with DNA vaccination is the need to bring sufficiently high quantities of DNA into the cells. This is the reason for the relatively low immunogenicity of DNA-based vaccines in comparison to expensive conventional vaccines. The researcher uses an innovative electroporation device, a prototype of which was provided by an American company, to create a local electrical field which renders the cell wall temporarily more permeable. “We are now about to start experiments with mice,” said Professor Öhlschläger outlining his next move.
New transport vehicles
The immunologist is always on the lookout for new challenges. That is why he has set himself an even more ambitious goal and is working on the development of RNA-based therapeutics. The idea arose one day while Öhlschläger was relaxing over a beer with a colleague from the faculty of chemistry. The joint RNA project also focuses on cancer therapy, not in relation to immunisation but to ways of effectively transporting substances into cancer cells. The researchers use so-called aptamers, three-dimensional nucleic acid structures that are highly specific for a certain protein. Aptamers are similar to antibodies, but considerably smaller and hence easier to navigate to the target site. They can be produced artificially and are also considerably cheaper than antibodies. Aptamers can, for example, be used as transport vehicles for markers. Genes can be attached to them, which can serve to introduce cytotoxic substances into the cells. Initial experiments have been successful and the two researchers are very optimistic. However, not everything that works well in the test tube also works well in the body. “One never knows what might happen next. That is what makes science so exciting,” said Prof. Öhlschläger.
mek – 18th May 2008
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